HLA-C variants associated with amino acid substitutions in the peptide binding groove influence susceptibility to Kawasaki disease

• Published in: Human immunology Vol. 80; no. 9; pp. 731 - 738
• Main Authors: Shimizu, Chisato, Kim, Jihoon, Eleftherohorinou, Hariklia, Wright, Victoria J., Hoang, Long T., Tremoulet, Adriana H., Franco, Alessandra, Hibberd, Martin L., Takahashi, Atsushi, Kubo, Michiaki, Ito, Kaoru, Tanaka, Toshihiro, Onouchi, Yoshihiro, Coin, Lachlan J.M., Levin, Michael, Burns, Jane C., Shike, Hiroko
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2019
• Subjects: Alleles; Amino Acid Sequence - genetics; Amino acid substitution; Amino Acid Substitution - genetics; Antigen presentation; Antigen Presentation - genetics; Binding Sites - genetics; Cohort Studies; Cytotoxic T cells; Gene Frequency - genetics; Genetic Predisposition to Disease; Genotype; Histocompatibility Testing; HLA-C; HLA-C Antigens - chemistry; HLA-C Antigens - genetics; Humans; Japan; Kawasaki disease; Mucocutaneous Lymph Node Syndrome - genetics; Peptides - genetics; Polymorphism, Single Nucleotide - genetics; Protein Binding - genetics; Protein Domains - genetics; T-Lymphocytes, Cytotoxic - immunology; Japan; Antigen presentation; GWAS; Kawasaki disease; Cytotoxic T cells; KD; HLA-C; SNV; Amino acid substitution
• ISSN: 0198-8859; 1879-1166
• DOI: 10.1016/j.humimm.2019.04.020

Kawasaki disease (KD) is a pediatric vasculitis caused by an unknown trigger in genetically susceptible children. The incidence varies widely across genetically diverse populations. Several associations with HLA Class I alleles have been reported in single cohort studies. Using a genetic approach, from the nine single nucleotide variants (SNVs) associated with KD susceptibility in children of European descent, we identified SNVs near the HLA-C (rs6906846) and HLA-B genes (rs2254556) whose association was replicated in a Japanese descent cohort (rs6906846 p = 0.01, rs2254556 p = 0.005). The risk allele (A at rs6906846) was also associated with HLA-C*07:02 and HLA-C*04:01 in both US multi-ethnic and Japanese cohorts and HLA-C*12:02 only in the Japanese cohort. The risk A-allele was associated with eight non-conservative amino acid substitutions (amino acid positions); Asp or Ser (9), Arg (14), Ala (49), Ala (73), Ala (90), Arg (97), Phe or Ser (99), and Phe or Ser (116) in the HLA-C peptide binding groove that binds peptides for presentation to cytotoxic T cells (CTL). This raises the possibility of increased affinity to a “KD peptide” that contributes to the vasculitis of KD in genetically susceptible children.